In immune response and its control, discrimination between self and nonself is the basis. The innate immune system and the adaptive immune system carry out this discrimination by the respective specific mechanisms and establish and maintain each mechanism not to response to self, so-called immune tolerance. Since activation of the innate immune response is known to be also involved in induction of the adaptive immune response, inhibition of the innate immune response is known to be also effective for inhibition of the adaptive immune response.
It has been revealed that in the adaptive immune system, after construction of a lymphocyte repertoire expressing random antigen receptors, the majority of autoreactive lymphocytes are eliminated by a central tolerance mechanism and the autoreactive lymphocytes still remaining at periphery are inhibited by a peripheral tolerance mechanism.
Though the recognition of an antigen by the adaptive immune system is characterized by the recognition of a specific molecular structure by a lymphocyte antigen receptor, the innate immune system is regarded to recognize the molecular pattern possessed by, for example, a pathogen, and many innate immune activating receptors including a Toll-like receptor (TLR) are known. In particular, the innate immune activation by nucleic acid is important for elimination of pathogens such as viruses and is simultaneously regarded to be involved in onset and exacerbation of various immune pathological conditions and is therefore drawing much interest. However, there are many unknown aspects in the discrimination mechanism by nucleic acid in the innate immune system, though receptor molecular groups, such as Toll-like receptor (TLR) 3, TLR7, TLR9, RIG-1-like receptor, DAI, and AIM2, have been identified as molecular groups carrying out immune responses activated by nucleic acid, the whole picture is still unclear (see, e.g., Non Patent Literatures 1 to 3).
In HMGB (high-mobility group box) proteins, it is known that HMGB1, HMGB2 and HMGB3 are present. These HMGB proteins are abundantly present in nuclei and are believed to be involved in chromatin structure and in control of transcription. In addition, they are known to be also present in cytoplasms and outside cells.
Patent Literature 1 describes a synthetic double-stranded nucleic acid or a nucleic acid analog molecule that inhibits binding between an extracellularly secreted HMGB1 protein and an advanced glycation end product receptor (RAGE) on a cell surface.
Patent Literature 2 describes a HMGB1 antagonist that inhibits interaction between the extracellularly secreted HMGB1 protein and the RAGE.
Non Patent Literature 4 describes that a base-free phosphorothioate deoxyribose homopolymer has a high affinity to TLR9 and TLR7 and acts as an antagonist of these TLRs.
Non Patent Literature 5 describes that though administration of a phosphorothioate oligonucleotide including a nucleotide sequence of 5′-TCCATGACGTTCCTGATGCT-3′ (SEQ ID NO: 37) to a mouse induces an IFN (interferon)-γ response, a phosphorothioate oligonucleotide including a nucleotide sequence of 5′-TCCATGAGCTTCCTGATGCT-3′ (SEQ ID NO: 38) does not cause such a response.